title: Oncogenic JAK1 and JAK2-activating mutations resistant to ATP-competitive inhibitors.
abstract: BACKGROUND
  Activating mutations in JAK1 and JAK2 have been described in patients with various hematologic malignancies including acute lymphoblastic leukemia and myeloproliferative neoplasms, leading to clinical trials with JAK inhibitors. While there has been a tremendous effort towards the development of specific JAK inhibitors, mutations conferring resistance to such drugs have not yet been observed.
  
  
  METHODS
  Taking advantage of a model of spontaneous cellular transformation, we sequenced JAK1 in selected tumorigenic BaF3 clones and identified 25 de novo JAK1 activating mutations, including 5 mutations already described in human leukemias. We further used this library of JAK1 mutation-positive cell lines to assess their sensitivity to ATP-competitive inhibitors.
  
  
  RESULTS
  While most JAK1 mutants were sensitive to ATP-competitive JAK inhibitors, mutations targeting Phe958 and Pro960 in the hinge region of the kinase domain rendered JAK1 constitutively active but also resistant to all tested JAK inhibitors. Furthermore, mutation of the homologous Tyr931 in JAK2 wild-type or JAK2 V617F mutant found in patients with myeloproliferative neoplasms also conferred resistance to JAK inhibitors, such as INCB018424, which is currently in clinical use.
  
  
  CONCLUSIONS
  Our data indicate that some activating mutations not only promote autonomous cell proliferation but also confer resistance to ATP-competitive inhibitors. In vivo, such a mutation can potentially occur as primary JAK-activating mutations but also as secondary mutations combining oncogenicity with drug resistance.
authors.affiliation: Ludwig Institute for Cancer Research, Avenue Hippocrate, 74, B-1200 Brussels, Belgium.
authors.forename: Tekla
authors.initials: T
authors.lastname: Hornakova
authors.forename: Lorraine
authors.initials: L
authors.lastname: Springuel
authors.forename: Julien
authors.initials: J
authors.lastname: Devreux
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dusa
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D023061:Gene Order; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D000255:Adenosine Triphosphate; D053613:Janus Kinase 1; D053614:Janus Kinase 2